The overall concern of this project is the regulation of cholesterol synthesis in animals, including humans. The focus of the work is enzyme HMG-CoA reductase, which catalyses the rate-limiting reaction of mammalian cholesterogenesis. We are studying the mechanisms whereby this reductase is interconverted between active and inactive forms in reactions that require MgATP and two converter proteins that we term the Activator and Inactivator. Part of our effort is directed towards discovering the detailed mechanisms whereby these converter proteins act in vivo to modulate the flow of carbon into cholesterol. Another, and more applied aspect, is the attempt to monitor the regulation of the reductase in human leukocytes. The object here is to develop a noninvasive technique for assessing the regulatory status of this enzyme in hypercholesterolemic individuals. Potential applications of this technique include screening drugs that act on the reductase and determining the kind of diet to be prescribed for given hypercholesterolemic individuals. BIBLIOGRAPHIC REFERENCES: Rodwell, V. W., J.L. Nordstrom and J.J. Mitschelen "Regulation of HMG-CoA Reductase," Advan. Lipid Res. 14, 1-74 (1976). Young, N.L., and V.W. Rodwell "Regulation of Hydroxymethylglutaryl-CoA Reductase in Rat Leukocytes," J. Lipid Res. 18 (in press, 1977).